Overexpression of high molecular weight FGF-2 forms inhibits glioma growth by acting on cell-cycle progression and protein translation.
In order to clarify the role of HMW FGF-2 in glioma development and angiogenesis, we over-expressed different human FGF-2 isoforms in C6 rat glioma cell line using a tetracycline-regulated expression system. Phenotypic modifications were analyzed in vitro and compared to untransfected cells or to cells over-expressing 18 kDa FGF-2 or all FGF-2 isoforms. In particular, we demonstrate that HMW FGF-2 has unique features in inhibiting glioma cell proliferation. HMW FGF-2 expressing cells showed a cell-cycle arrest at the G2M, demonstrating a role of HMW FGF-2 in controlling the entry in mitosis. Moreover, hydroxyurea was ineffective in blocking cells at the G1S boundary when HMW FGF-2 was expressed. We also show that the HMW FGF-2 isoforms inhibit 4E-BP1 phosphorylation at critical sites restoring the translation inhibitory activity of 4E-BP1. In vivo, inhibition of tumor growth was observed when cells expressed HMW FGF-2. This indicates that HMW FGF-2 inhibits tumor growth in glioma cells by acting on cell-cycle progression and protein translation.
Lemiere
Sylvie
S
INSERM, U920 Talence, F-33405, France.
Azar
Rania
R
Belloc
Francis
F
Gürsel
Demir
D
Pyronnet
Stéphane
S
Bikfalvi
Andreas
A
Auguste
Patrick
P
D000818:Animals; D002453:Cell Cycle / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008970:Molecular Weight; D014176:Protein Biosynthesis / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D051381:Rats; D014162:Transfection; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D020033:Protein Isoforms; D016222:Fibroblast Growth Factor 2